Mitochondrial metabolism is a tightly regulated process that plays a central role throughout the lifespan of hematopoietic cells. Herein, we analyze the consequences of the mitochondrial oxidative phosphorylation (OXPHOS)/metabolism disorder associated with the cell-specific hematopoietic ablation of apoptosis-inducing factor (AIF). AIF-null (AIF ) mice developed pancytopenia that was associated with hypocellular bone marrow (BM) and thymus atrophy. Although myeloid cells were relatively spared, the B-cell and erythroid lineages were altered with increased frequencies of precursor B cells, pro-erythroblasts I, and basophilic erythroblasts II. T-cell populations were dramatically reduced with a thymopoiesis blockade at a double negative (DN) immature state, with DN1 accumulation and delayed DN2/DN3 and DN3/DN4 transitions. In BM cells, the OXPHOS/metabolism dysfunction provoked by the loss of AIF was counterbalanced by the augmentation of the mitochondrial biogenesis and a shift towards anaerobic glycolysis. Nevertheless, in a caspase-independent process, the resulting excess of reactive oxygen species compromised the viability of the hematopoietic stem cells (HSC) and progenitors. This led to the progressive exhaustion of the HSC pool, a reduced capacity of the BM progenitors to differentiate into colonies in methylcellulose assays, and the absence of cell-autonomous HSC repopulating potential in vivo. In contrast to BM cells, AIF thymocytes compensated for the OXPHOS breakdown by enhancing fatty acid β-oxidation. By over-expressing CPT1, ACADL and PDK4, three key enzymes facilitating fatty acid β-oxidation (e.g., palmitic acid assimilation), the AIF thymocytes retrieved the ATP levels of the AIF cells. As a consequence, it was possible to significantly reestablish AIF thymopoiesis in vivo by feeding the animals with a high-fat diet complemented with an antioxidant. Overall, our data reveal that the mitochondrial signals regulated by AIF are critical to hematopoietic decision-making. Emerging as a link between mitochondrial metabolism and hematopoietic cell fate, AIF-mediated OXPHOS regulation represents a target for the development of new immunomodulatory therapeutics.
Introduction: The Antibody-Drug Conjugates (ADCs)-based therapy has revealed a field of perspectives by increasing the specificity and the efficacy of the anti-tumoral drug treatment. McSAF is a company focused in bio-organic and bioconjugates chemistry and has developed a new linker technology solution, allowing to improve ADCs homogeneity and stability resulting in a higher anti-tumoral effect on a HER2-positive breast tumor model (BT-474 cell line) and a CD30-positive non-Hodgkin's lymphoma model (Karpas-299 cell line). Methods: The anti-tumoral activity of McSAF-ADCs was tested both in vitro and in vivo. In both cell line models, an MTS-based cell viability assay has been performed in presence of the standard of care (SOC, Kadcyla® (T-DM1) = Trastuzumab emtansine, or Adcetris® = Brentuximab vedotin) or the equivalent McSAF-ADCs at different concentrations for 72 to 96 hours. In vivo studies were conducted with xenograft models of HER2-positive tumors in Balb-c nude mice and CD30-positive lymphoma in CB17 SCID mice. After tumor induction, animals bearing well-established tumors (≈100-200 mm3) were randomized and treated once or twice with vehicle, SOC or McSAF-ADCs at one or two doses. During the study course, the animals were monitored for several weeks for their behavior, body weight and tumor volume. Results: In the HER2-positive breast tumor model, in vitro experiments revealed a higher cytotoxicity of MF-TTZ-MMAE (IC50 = 1 nM) on BT-474 cell line compared to the SOC (IC50 ≈ 100 nM). In vivo, the treatment with MF-TTZ-MMAE was well tolerated at all tested doses (1 and 5 mg/kg). At 5 mg/kg, the MF-TTZ-MMAE compound induced a full regression of tumors after second treatment. At the end of the study, all animals treated with MF-TTZ-MMAE were still tumor free, seven weeks after end of treatment, which was not observed on animals treated with T-DM1 (only 25% tumor-free animals). In the CD30-positive non-Hodgkin's lymphoma model, the MTS assay revealed similar efficacy for brentuximab vedotin and MF-BTX-MMAE (IC50 ≈ 0.1 nM) on Karpas-299 cell line. In vivo, the treatment with MF-BTX-MMAE was well tolerated at all tested doses (0.5 and 1 mg/kg). The single treatment with MF-BTX-MMAE had a marked, dose dependent, anti-tumoral efficacy with 40% and 100% of animals showing complete regression at the end of the study (9 weeks after treatment) for doses of 0.5 mg/kg and 1 mg/kg respectively. And again, the treatment with MF-BTX-MMAE at 0.5 mg/kg resulted in a higher tumor growth inhibition and better survival than with the clinical equivalent ADC Adcetris® at the equivalent dose. Conclusion: Altogether, these promising results reveal that improvement of ADCs stability and homogeneity leads to a higher anti-tumoral activity as tested both in vitro and in vivo HER2-positive and CD30-positive tumor models. Citation Format: Jean-Francois Mirjolet, Audrey Bertaux, Samira Benhamouche-Trouillet, Pascal Grondin, Ambrine Sahal, Guillaume Serin, Ludovic Juen, Christine Baltus, Camille Gély, Ofelia Feuillâtre, Audrey Desgranges, Marie-Claude Viaud-Massuard, Camille Martin. ADCs optimization lead to a significant anti-tumoral activity in lymphoma and breast tumor xenograft mouse models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4115.
Preclinical and clinical studies have shed light on the beneficial role of bacteria for cancer therapy. Indeed, these studies have demonstrated that these microorganisms have beneficial properties that allow them to selectively colonize tumor and that they could also be considered as predictive drug efficacy biomarkers. Based on these results, bacteria are now used for delivering therapeutic components or for shaping the gut microbiota. Ultimately these approaches lead to the activation of an immune response against the tumor. Owing to our scientific and technological expertise in manipulating microbes, we propose tailor-made strategies for investigating the efficacy of bacteria-based treatments and/or the effect of therapies on the microbiota both in vitro and in vivo. Different methods/analyses can be used for culturing, detecting, quantifying, identifying and localizing live bacteria (e.g. counting of CFUs, PMA-qPCR, 16 rRNA gene sequencing, mass spectrometry, bioluminescence) in simple or complex samples (e.g. from culture of single bacterial species to rodent/human stools or other tissues). In addition, a continuum of assays allows us to evaluate the impact of bacteria or derived products directly on tumor and/or immune cells (e.g. immune infiltrate and phenotyping, cytokine/chemokine profiling, tumor burden). We will highlight some results obtained in a cancer context such as the immunostimulatory properties of bacteria or their derivatives, the selective colonization of tumor tissue by bacteria, the benefits in delivery of therapeutic proteins or antigens by bacteria, the impact of tumor engraftment/growth on gut microbiota, the effects of chemotherapeutic agents on intestinal microflora, the consequences of supplementation with bacteria or antibiotics treatment on the response to immune checkpoint inhibitors. Altogether these data demonstrate that bacteria are now allies in the treatment of cancer and that our comprehensive platform is suitable for evaluating both in vitro and in vivo therapeutics developed from bacteria (individuals, consortium or derived products; native or modified). All these technologies can be also applied to develop novel therapeutic strategies for inflammatory and infectious diseases known to increase the risk of cancer development. Citation Format: Sylvie Maubant, Marie Leblanc, Elisabeth Bertrand, Audrey Bertaux, Loic Morgand, Maxime Ramelet, Marie Lux, Olivier Duchamp, Fabrice Vivani. Using individual or a consortium of bacteria for immuno-oncology research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3053.
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